DE1443664A1 - Process for the preparation of pharmaceutically active derivatives of 2-aminoindane - Google Patents

Description

Dr. Expl.

Chemical works Albert. Wlesbaden-Biebrlch. Albertatr. 10-14 patent applica message

"Process for the preparation of pharmaceutically active derivatives of 2-Amlnolndana ^w ■ * ■

Derivatives of 2-aminoindane, in particular N-substituted ones, have been described several times in the literature. Einice im Nuclear alkoxylated derivatives of 2-arainoindane, optionally alkylated on the nitrogen, have an analytical nature Effect. Other N-substituted derivatives of 2-aminoindane have a bronchodilator effect.

It is also known that the 1,1-diphenylpropylO-amine grouping is pharmacologically active. The N- (I ¹ -phenylisopropyl) -1, 1-diphenylpropyl - ^ - amine has a coronary effect. Surprisingly, it has now been found that previously unknown N-diary1-alkyl derivatives of the 2-aminoindane of the general structure

(D

where R ₁ to R ₈ denote hydrogen, alkyl or alkoxy radicals and can be identical or different and in each case in the aryl radical also in the same or different

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Meaning can occur several times, H ₄ and R ₈ denote hydrogen or an alkyl radical and can be identical or different, R ₆ denotes hydrogen or methyl and A denotes 0 to 3 methylene groups, especially in the form of their pharmaceutically acceptable acid addition compounds an excellent coronary effectiveness with comparatively have low peripheral vascular effects. In the radicals R ₁ to R ₅ , the alkyl or alkoxy radicals should not have more than 5, preferably not more than 2, carbon atoms. In addition, the residues attached to a benzene nucleus should not contain more than 4 carbon atoms.

Compounds of structure (I) can be used according to the invention manufacture in the following ways:

1) Amines of the general formula are used

in which R ₃ , R ₉ and R _{6 have} the meanings given above, at elevated temperature, optionally under pressure, with halogen compounds of the general formula

X-CH-A-CH (III)

in which R ^, R _x , R ₄ and A have the meanings given above and X is a halogen with an atomic weight of at least 35, that is, above all chlorine or bromine, but optionally also iodine. (Examples 1 to 3). .

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2) Amines of the general formula II are condensed with oxo compounds of the general formula

in which R., R ₈ , R ₄ and A have the meanings given above, and the reaction products are hydrogenated, possibly in isolated form, in the presence of a suitable hydrogenation catalyst. (Examples 4 and 5) · Conirer such as palladium-carbon, Raney nickel and possibly also Raney cobalt in question.

Z) One uses ketones of the general formula

-O

(V)

to, in which R 1 and R _{4 have} the meanings given above, with amines of the general formula

HR ₆ N-CH-AC

(VI)

in which R., R _x YR ₄ , R ₄ and A have the meanings given above, and the intermediates are hydrogenated in the presence of a suitable hydrogenation catalyst, for example those mentioned above. (Examples 6-8).

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Acid amides of the general formula are reduced

evil)

in which H. to H ₃ , R ₃ , R ₆ and A have the meanings given above, under conditions known per se. For example, lithium aluminum hydride is used in an anhydrous solvent that does not react with lithium aluminum hydride, for example tetrahydrofuran, or on a copper chromium oxide catalyst. The acid amides can be prepared from the corresponding acid halides by reaction with the \, y ^ ß /? win corresponding amines. (Examples 9 and 10)., ^ 0 'ΐ''''^ l

The above embodiments are generally carried out at an elevated temperature from 0 to the point of decomposition, preferably from 70-150 ° C. In general, normal pressure is used, but increased pressure can also be used. The reactions are carried out in the presence of solvents, ζ · Β. of hydrocarbons of an ipiatic or preferably aromatic nature, such as benzene, oil, the various xylenes, acetates such as methyl or propylene, dioxin. or - "" ^iÄ alcohols such as methanol, ethanol, iso-propanol and the various butanols "^ The yield is good. The raw construction yield (about 80-95 pounds as _a product) is often between 80 and $ 0 $ in theory. The yield of pure products naturally depends on the purity requirements.

The acid addition compounds can consist of the most varied Acids, e.g. hydrochloric acid, hydrobromic acid, tartaric acid, Citric acid, malic acid, gluconic acid, adipic acid and Lactic acid can be obtained.

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The compounds prepared according to the invention have a very low toxicity and are cardiovascular and cardiovascular. Particularly striking is the very good vmü- specific coronary activity with relatively little peripheral activity.

example 1

A solution of 2 g of 2-aminoindane and 3.68 g of ß-phenyl-ß (p-tolyl) propyl-chloride in 12 ml of ethanol is heated for 6 hours in a sealed tube at 120 ⁰ C. After cooling, the ethanol is distilled off. After a Umkrlstallisation from isopropanol there is obtained the 2 - [/ - phenyl-l- (p-tolyl) -propylamino] -indan-hydro-chloride of melting point 207-208 C. ^e

Example 2

A solution of 2.92 g of 1-methyl-2-aminoindan and 4.89 g Q-Phenyl-ß- (p-tolyl) propyl chloride in 15 ml of ethanol is heated in the bomb tube to 125 ° C for 6 hours. To

ORIGINAL BATHROOM

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When it cools, the hydrochloride of 1-methyl-2 - [/ - phenyl-I - * (p-tolyl) -propyl-amino-indane precipitated with ether is filtered off with suction and recrystallized from isopropanol. It melts with a dark color at 224 - 227 ⁰ C.

Example 3

To a heated solution of 5 g of 2-amino-5 # 6-dimethoxyindane in 70 ml of dried benzene, 3 »17 g of ß-phenyl-ß- (p-tolyl) propyl chloride in 25 ml of benzene added dropwise. Afterwards it will be 20 hours on Heated to reflux. It drops the hydrochloric! of the amine used; by cooling, concentrating the solution and adding ether, the separation is completed. From the filtrate falls on the addition of ether isoher Hydrochloric acid of the hydrochloride of 5,6-dimethoxy-2- [Jf-phenyl-J- (p-tolyl) -propylaminoj-indane. After recrystallization from isopropanol, the compound melts below at 226-228 ° C Brown color.

Example 4

To a mixture of 3.8 g of 2-aminoindane and 5.06 g Diphenylacetaldehyde is added to about 10 ml of methanol « whereupon / crystallization occurs. The resulting Schiff base is recrystallized from isopropanol, redissolved in Ieopropanol and in the presence of Raney -! - Ni disgust as a catalyst at 52 At and room temperature Hydrogenated for 6.5 hours. The solution is made of catalyst filtered off and the hydrochloride of 2- (ß, ß-Diphenyläthylamlno) -Indane precipitated with hydrochloric acid. After recrystallization by dissolving lh isopropanol and When filled with ether, it has a melting point of 205-208 ° C with simultaneous decomposition.

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Example 5

5 * 0 g of 2-aminoindane and 8.4 g of benzhydrylacetone are refluxed in 100 ml of dried benzene for 30 minutes. The benzene and the water formed are then distilled off and the residue is taken up in isopropanol. After adding 1 g of palladium on charcoal (Pd content about 10 $) as a catalyst, at 85'C and 80 At. Hydrogen pressure hydrogenated for 6 hours. The catalyst is filtered off, the filtrate is concentrated and the hydrochloride of 2- (i, | -Diphenyla-methy1-propylamine) -indane is precipitated with hydrochloric acid. After recrystallization from isopropanol, the compound melts at 192 - 194 ^° C.

Example 6

13.2 g indandn- (2) and 21.1 g /, Ϊ-diphenylpropylarain are dissolved in 250 ml .Methanol and in the presence of 1 - 2 g Palladium on carbon (Pd content about 10 *) as a catalyst at 60 * C and 80 At. Hydrogen pressure hydrogenated for 5 hours. Of the The catalyst is filtered off and the filtrate old concentrated hydrochloric acid is added, whereupon the hydrochloride Id de · 2- (jf, f-DiphenylpropylaHji.no) -indane fails. Egg is sucked off and made from isopropanol (if necessary with the addition of activated charcoal) uncrystallized. It melts at 2 <t? - 246 * C under Darkening.

After the addition of tartaric acid in methanol (and possibly ether), the acid tartrate of 2- (7i / -Diphenylpropylamino) -indans with a melting point of 200-203 * 0 precipitates from the filtrate of the hydrogenation batch. The acid malate is obtained in the same way with apple sour. This has a melting point of 170-173 * 0. \

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Example 7 ...

phenyl
2.7 g of Jf, J-bis-Cp-methcocy-J-propylamine and 1.32 g of indanone- (2) are dissolved in 130 ml of isopropanol and in the presence of Raney nickel as a catalyst at 60 ° C. and 80 ° C. Hydrogen pressurized for 5.5 hours. After cooling, the catalyst is filtered off and the hydrochloride of 2- [f, i-bis- (p-anieyl) -propylamino] -indane is filled from the filtrate *, possibly after concentration of the solution, by means of ethereal hydrochloric acid. After recrystallization from isopropanol, the compound melts at 187 - L89 ^# C.

Example 8

5 * 0 g of ίΤ-benzhydrylpropylamine and 2.94 g of xndanone- (2) are implemented as in Example 7. The hydrochloride of 2- (Jf-Benzhydrylpropylamino) -indane melts after recrystallization from isopropanol at 182-183 ° C.

Example 9

A solution of 3.3 g of N-indanyl- (2) -fl-mesityl-hydrocinnamic acid amide in 70 ml of dry tetrahydrofuran is added to 1 g of lithium aluminum hydride in 50 ml of tetrahydrofuran with constant stirring dripped. The mixture is refluxed for 8 hours. The excess lithium aluminum hydride is released after cooling decomposed with 10 ml isopropanol and 5 ml water and sucked off the precipitate. The filtrate is mixed with water, whereby the 2- (Jf-phenyl- <f-roe8ityl-propylamino) -indane separates. It is extracted and the hydrochloride with ethereal hydrochloric acid pleases. After recrystallization from isopropanol, it melts with a dark color at 258-26 ° C.

Example 10 A slurry of 5 g of N-indanyl- (2) -e- (p-methoxyphenyl) -

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hydroziratsäureamid in 140 ml of tetrahydrofuran is under vigorous stirring to 2 g of lithium aluminum hydride in 100 ml of tetrahydrofuran added dropwise. Then 20 hours under RUokflufl cooked. After cooling, add excess lithium aluminum hydride with 12.5 ml of isopropanol and 6.5 ml Water decomposes and the precipitate is sucked off. The piltrate is mixed with water; the 2- [Y- (p-methoxyphenyl) -y-phenyl-propylamine] -indan separates away. It is extracted using essential hydrochloric acid as a Hydrochloric! pleases and recrystallized from isopropanol. Melting point 191-193 * C7

The effect and Toxizltät of the compounds prepared according to Examples 1 and 6 will be compared in the following table, a _v-known preparation, wherein always the same amounts were used.

Tabel Substance LDe _n intravenous effect on the Langendorff

k- < AM ,, u., .. hearts. Increase compared to the mouse _{over the} | t4 ^ö

2- [J-phenyl-J-

(p-tolyl) -propyl-

amino] -indan Jl. 9 mg / kg 110 %

(Example 1)

2- (I ./- Diphenyl-

propyl-araino) - 24.9 mg / kg 100 %

indan (example 6)

H- [l «-phenyl-iso-

propylj-l, l-di- 14.5 mg / kg 100 %

phenyl propyl

There were no differences in the measurement of the increase in flow in the isolated rabbit ear according to the Krawkow-Plssemski method. For vessel formation, 1 - («- hydroxyphenyl) -2 -amino-ethanol hydrochloride (0.5 t / ml) was added to the nutrient fluid.

From the above it follows that the. substances according to the invention are significantly less toxic with the same or better absolute and specific effect. So you have an essential Greater therapeutic breadth.

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Claims (1)

Claims Process for the preparation of pharmaceutically active derivatives of the 2-Amlnoindans of the form «! (D wherein R ₁ to R ₃ are hydrogen, AIlQfI- or alkoxy radicals and can be identical or different and in each case in the aryl radical in the same or different meanings occur several times Kum / s »H ₄ and B is ₉ is hydrogen or a Alkylreat and be identical or different can, Hj hydrogen or methyl and A 0 to 3 methylene group !! means « where in the best R ₁ to H ₈ the alkyl or alkoxy radicals do not contain more than 3 and the reagents that oxidize a benzene nucleus contain no more than 4 carbon atoms» characterized by the fact that one
1) Amines of the general formula 3ffi «H (II) with halogen compounds of the general formula (III) 809607/044 BATH umaetzt or 2) Amines of the general formula II with oxo compounds the general formula OC-A-CH (IV) condensed and the reaction products hydrogenated or 3) ketones of the general formula (V) with amines of the general formula (VI) reacted and hydrogenated the resulting intermediates or 4) SMureamide of the general formula -NRg-CO-A-CH (VII) 809807/0 AA7 ^BAD original hydrogenated, where in the formulas XI to VIZ the radicals R. to R ₄ and A have the meaning given above and X is a halogen with an atomic weight of at least 35. 2. Compounds of the formula I given in Claim 1, in which R 1 to R ₆ and A have the meaning given » Dr.KIr / tk August 24, 1964 BAD ORlGINAi- 609807/0447 I.